JP2584829B2 - Method for producing 9 (11) -dehydrosteroid - Google Patents

Description

The present invention relates to a method for producing 9 (11) -dehydrosteroid from a corresponding 9-α-hydroxy compound by a dehydration treatment thereof.

Of the 9 (11) -dehydrosteroids, 9 (11) -dehydroandrostane and 9 (11) -dehydropregnane constitute an important group of intermediates in the synthesis of steroid formulations. The intermediate is 9-halogen- and / or
It can be easily converted to a steroid using an 11-hydroxy substitution, which is a characteristic substitution of many compounds belonging to the corticosteroid group.

[Conventional technology]

Various methods are already known for the production of 9 (11) -dehydrosteroids, for example using the dehydration reaction of the corresponding 9-α-hydroxy compounds.

U.S. Pat. No. 3,065,146 describes a dehydration reaction using thionyl chloride in pyridine for the preparation of 9 (11) -dehydroprogesterone. The reaction method is 9-α
It is also used for the dehydration of hydroxyandrost-4-ene 3,17-dione.

Dutch Patent Application No. NL7802302 demonstrates that significant amounts of the 8 (9) -dehydro isomer are also formed using the dehydration process described above. This fact leads to a low yield of the desired compound and has the additional disadvantage that the removal of the undesired isomer is extremely complicated and expensive.

East German Patent DL 20528 provides a method for easily producing 9 (11) -dehydrosteroids, i.e. boiling a solution of the corresponding 9-α-hydroxy compound with an aromatic sulfonic acid. Although the use of 9-α-hydroxytestosterone is specified, the examples only involve pregnane. This patent specification contains only a few ambiguous data on yield and purity. This method has failed when applied to 9-α-hydroxyandrostane. Literature (CGBergstrom and R.
As confirmed in B. Dodson (Chemistry and Industry, 1530 (1961)), no 9 (11) -dehydroandrostane is produced.

German Patent Application DE 2806687 describes an improved method. That is, the 9-α-hydroxyl group of the androstane compound is first converted to 9-
-Α-OSOR-, where R is (1-4C) alkyl, phenyl or substituted phenyl. This is then boiled in benzene using silica gel or alumina and an acid to remove the sulfine (desu).
lfination reaction) to give the desired 9 (11) -dehydro compound in a yield of 85% or more, and the production ratio of 9 (11) -dehydro isomer: 8 (9) -dehydro isomer is 98: 2 or more. It is. However, despite the good yield of the 9 (11) -isomer, the additional isomer fractionation step constitutes a practical as well as an economic disadvantage.

Probably the reason that the prior art researchers believed that p-toluenesulfonic acid was unsuitable for the dehydration of 9-α-hydroxyandrostane was a German patent application.
It appears that DE 2814747 did not explicitly mention the use of aromatic sulfonic acids. Good results were obtained with non-aromatic oxygen-containing acids.

[Disclosure of the Invention]

The present invention provides a process for producing 9 (11) -dehydrosteroids in high yields by dehydration of the corresponding 9-α-hydroxysteroids, which is undesirable in such products.
The (9) -dehydro isomer is only detected in insignificant amounts.

It is surprising that it has been found in the present invention that 9-α-hydroxysteroids are dehydrateable, preferably in the presence of a Lewis acid in solution. Suitable Lewis acids are, for example, ferric chloride, boron trifluoride and complexes thereof, such as etherates, antimony pentachloride and titanium tetrachloride, but other Lewis acids, such as aluminum chloride and stannous chloride, may be used as well. . More preferably, a boron trifluoride complex is used, which is an inexpensive and easily available reagent. For an extensive survey on Lewis acids see the literature [Acta Chemica Scandinavica B40 (1
986) 522-533].

 The above Lewis acids can be shared with silicon dioxide.

The present invention provides compounds of formulas I and III Applied to androstane and pregnane steroids having the usual steroid structure represented by
This gives compounds II and IV.

The invention is applicable in both cases, whether or not the carbon atoms and the pregnane side chains of the steroid are substituted and whether they are interconnected by a double bond. 9 (11) - there should be one hydrogen atom at least on carbon atom C ¹¹ in structure I and III for the dehydration reaction performed.

Although the organic solvent can also be used any organic solvent suitable solvents are benzene, a toluene and methylene chloride, the BF ₃ and its complexes, acetic acid or acetic anhydride can be used. Reaction temperatures vary from room temperature to reflux temperature. Depending on the reaction conditions and the catalyst chosen, the reaction time varies from 5 minutes to 3 hours.

It is common for steroids with groups sensitive to particular Lewis acids (eg, 17-α-hydroxy, 20-ketopregnan for boron trifluoride complexes) to be protected before the dehydration reaction.

The great benefit obtained by following the present invention is, as already mentioned, that the resulting 9 (11) -dehydroandrostane contains little or no 8 (9) -dehydro isomer of the interfering substance. . The isomer cannot be distinguished from the 9 (11) -isomer also by thin-layer chromatography, since the _Rf value hardly changes. C in yet sensitive if 360MH _z NMR- device both isomers
(4) H- shift a small amount of 8 (9) to the extent of 0.5% by using a difference in 12H _z between (s) - can detect dehydroepiandrosterone steroids. A specific HPLC (High Performance Liquid Chromatography) analysis method has been developed to examine the state of formation of the reaction product, and detection based on a slight difference in residence time between both isomers is possible. As a special case, the relevant residence times in the dehydration reaction of 9-α-hydroxyandrost-4-en-3,17-dione are as follows: 4.14 minutes 9-α-hydroxyandrost-4-ene -3,17-dione 9.26 min Androsta-4,8-diene-3,17-dione 9.73 min Androsta-4,9 (11) -diene-3,17-dione The above retention time is characteristically developed. It should be understood that they represent the values obtained from a given HPLC system, ie, the values characterized by some corresponding mobile and stationary phases.

〔The invention's effect〕

It will be appreciated that the removal of the 8 (9) -dehydro by-product is difficult and therefore an expensive operation. In products manufactured according to the present invention, NMR or HPLC-
When tested by analysis, no 8 (9) -dehydro isomer was detected.

Another advantage of the present invention is that the reaction is carried out in a conventional organic solvent, so that the product after the dehydration treatment can be directly used for the reaction in a multi-step method without isolation. The above benefits constitute a valuable feature, especially when anhydrous reaction conditions are desired.

Thus, the present invention provides an inexpensive and convenient method for producing an important group of 9 (11) -dehydrosteroids in high yield and purity.

〔Example〕

The following examples illustrate the invention. NMR-spectrum 3
It was recorded using the 60MH _Z proton NMR and 20MH _Z C ¹³ NMR. NMR data is in delta units [delta (ppm) units downf
ield from TMS]. All percentages are given by weight unless otherwise indicated.

Example 1 Ferric chloride / silicon dioxide reagent (2.4 g) [This reagent was prepared according to the Fadell-Cyrone method (A. Fadel and J. Salauen, Tetrah)
edron 41, 413, 1985)] and 9-α
A suspension of -hydroxyandrost-4-en-3,17-dione (0.40 g) in anhydrous benzene (25 ml) was heated at reflux for 2 hours. TLC (silica gel; toluene / acetone)
As a result of the examination according to 3: 1), the above-mentioned starting material was completely converted mainly to Androstar 4,9 (11) diene-3,17-dione. The reaction mixture was poured onto a chromatography column and eluted with acetone. The eluate was evaporated to dryness, the residue was dissolved in acetone, water was added and the acetone was removed by evaporation under reduced pressure. The resulting precipitate was filtered, washed with acetone / water (1: 2) and dried.

The yield of Androsta-4,9 (11) -diene-3,17-dione was 0.16 g. Examination by NMR (< ¹³ > C and < ¹ > H) revealed no 8 (9) -dehydro isomer.

The mother liquor still contained additional product as determined by TLC.

_{NMR (CDCl 3): 0.891 (} C 18 -H 3), 1.369 (C 19 -
_{H 3), 5.56 (C 11} + H), 5.75 (C 4 -H).

Example 2 A suspension of anhydrous ferric chloride (0.2 g) and 9-α-hydroxyandrost-4-en-3,17-dione (0.50 g) in dry benzene (25 ml) was heated at reflux for 2 hours. . TLC
(Silica gel; toluene / acetone 3: 1) According to the analysis, the reaction was not completed, and the main product was Androsta-4,9 (11)
-Diene-3,17-dione.

Example 3 9-α-hydroxyandrost-4-ene-3,17-
To a stirred solution of dione (604 mg) in methylene chloride (20 ml) was added antimony pentachloride (1.28 ml). The mixture was stirred at room temperature for 1.5 hours,
Water (20 ml) was added to the dark reaction mixture. Ten
Stirred vigorously for minutes and filtered to remove the aqueous layer.

The organic layer was washed with 1 molar sodium bicarbonate solution and water (3x) before treating the organic solution with charcoal and sodium sulfate, filtering and evaporating the filtrate to dryness. The residue was crystallized from acetone to give crude androstar.
4,9 (11) -Diene-3,17-dione (139 mg) was produced.

Example 4 9-α-hydroxyandrost-4-ene-3,17-
A suspension of dione (3.02 g) in benzene (150 ml) was stirred while boron trifluoride etherate (6.31 g) was added.
ml) was added. The mixture was heated at reflux for 0.5 h, at which time a violet solution was obtained. The mixture was then cooled to room temperature and water (15 ml) was added and the violet color turned yellow. The organic layer was separated, washed twice with water (15 ml), added with methanol and evaporated to dryness. The crude product was crystallized sequentially from acetone and ethanol to give pure androster.
4,9 (11) -Diene-3,17-dione (2.3 g) was produced; mp 204-205.5 ° C.

_{NMR (CDCl 3): 0.891 (} C 18 -H 3), 1.371 (C 19 -
_{H 3), 5.57 (C 11} -H) and 5.76 (C ₄ -H).

Example 5 9-α-hydroxyandrost-4-en-3,17-
Dion [purity 97.5%] (3.02g) dried benzene (150m
While stirring the suspension in l), boron trifluoride methanol complex (50 mmol; 5.48 ml) was added thereto.

The reaction mixture was heated at reflux for 40 minutes and then cooled to room temperature, after which the reaction mixture was stirred and water (15 ml) was added thereto. One hour after stirring, the mixture separated into two layers. The organic phase was washed twice with water and then evaporated under reduced pressure to a purity of 89.5% and a yield of 92.4% at 2.56%.
g of Androsta-4,9 (11) -diene-3,17-dione were provided.

NMR ⁽¹³ C and ¹ H) and by HPLC analysis. 8 (9) -
No dehydro isomer was present.

Example 6 9-α-hydroxyandrost-4en-3,17-dione [purity 97.5%] (3.02 g) in dry benzene (150 ml)
While stirring the suspension therein, boron trifluoride acetate complex (6.94 ml) was added. The reaction mixture was heated at reflux for 30 minutes and then allowed to cool to room temperature before adding water (15 ml) with stirring of the reaction mixture. After 1 hour of stirring, the two layers separated. The organic layer was washed twice with water and evaporated to dryness under reduced pressure to give 2.83 g of Androsta-4,9 (11) -diene-3,17-
Dione was provided; purity 95.4%, yield 97.5%. The 8 (9) -dehydro isomer was absent according to NMR (< ¹³ > C and < ¹ > H) and HPLC analysis.

Example 7 9-α-hydroxyandrost-4-ene-3,17-
Dion [purity 97.5%] (3.02g) dried benzene (150m
While stirring the suspension in l), titanium tetrachloride (6.48 ml; 50 mmol) was added thereto. The reaction mixture was heated at reflux for 42 hours and after cooling to room temperature the mixture was washed three times with water,
It concentrated under reduced pressure to dryness. According to HPLC analysis, this crude product contained 0.40 g (14.4% yield) of androsta-4,9 (11) -diene-3,17-dione. The 8 (9) -dehydro isomer was not detected.

Example 8 9-α-hydroxy-3-methoxyandrosta-3,
5-Dien-17-one (3.16 g) in dry benzene (150 m
While stirring the suspension in l), boron trifluoride acetate complex (6.94 g) was added thereto. The reaction mixture was heated for 30 minutes and after cooling to room temperature, the reaction mixture was washed with water (15 ml)
For 10 minutes. Further addition of water and ethyl acetate resulted in two layers. The organic layer was washed with water until the pH value became neutral, dried, and concentrated under reduced pressure to obtain 2.73 g of Androsta-4,9.
This gave (11) -diene-3,17-dione [purity 87% (HPLC)].

Example 9 9-α, 21-dihydroxypregna-4,16-diene
A suspension of 3,20-dione (0.40 g) in dry benzene (25 ml) was stirred with an anhydrous ferric chloride / silicon dioxide reagent [prepared as described in the literature (Tetrahedron 41, 413 (1985)). The reaction mixture was heated under reflux for 45 minutes, then cooled to room temperature, poured onto a short chromatography column (silica gel), and eluted with acetone. The solid was dissolved in methylene chloride and water, the organic layer was washed twice with water, concentrated under reduced pressure and dried to give a crude product (0.28
g). This is chromatographed (silica gel;
Purification with toluene / acetone (5/1) gave 21-hydroxypregna-4,9 (11), 16-triene-3,20-dione.

The 8 (9) -dehydro isomer was not detected (NMR).

_{NMR (CDCl 3): 0.908 (} C 18 H 3), 1.371 (C 19 H 3), 4.4
_{^{5,4.54 (C 21 H 2),}} 5.56 (C 11 H), 5.75 (C 4 H), 6.78
(C ¹⁶ H).

Example 10 17-β-cyano-9-α, 17-α-dihydroxy-16
-Β-methylandrost-4-en-3-one (5.75
To a stirred suspension of g) in benzene (250 ml) was added boron trifluoride etherate (250 ml). The reaction mixture was stirred for 15 minutes and after cooling to room temperature, ethyl acetate (200 ml) and water were added. The organic layer was separated, washed three times with water, filtered, and concentrated under reduced pressure to dryness. This crude product was crystallized from ethyl acetate and purified to give 3.39 g of 17-β-cyano-17-α-hydroxy-16-.
β-Methylandrosta-4,9 (11) -dien-3-one was provided.

 M.P. 189-191C (decomposition).

_{NMR (CDCl 3): 0.929 (} C 18 H 3), 1.31 (C 16 H 3), 1.34
_{^{7 (C 19 H 3),}} 5.58 (C 11 H), 5.75 (C 4 H).

Example 11 A suspension of 17-β-cyano-9-α, 17-α-dihydroxyandrost-4-en-3-one (6.58 g; 20 mmol) in benzene (300 ml) was added thereto with stirring. Boron trifluoride etherate (12.6 ml; 100 mmol) was added. After heating at reflux for 20 minutes, the reaction mixture was cooled to room temperature. Methanol (30 ml) was added to the reaction mixture to give a clear solution.

The reaction mixture was cooled in an ice bath, saturated with hydrogen chloride gas and stirred in a sealed bottle at room temperature for 17 hours. After cooling in an ice bath, ice (150 g) was added to the reaction mixture. The organic layer was separated and washed three times with water. Merge the aqueous layers (500ml) at room temperature
After stirring for an hour, the product crystallized. The crystals were filtered, washed with water and dried. This crude product (5.14 g) was purified on silica gel using diethyl ether. 3.81 g (55%) of pure methyl 17 crystallized from diethyl ether.
-Α-hydroxy-3-oxoandrostane-4,9 (1
1) -Diene-17-α-carboxylate was provided. NMR
According to ⁽¹³ C and ¹ H) 8 (9) - dehydro isomers was present.

 M.P. 199.5-197C.

_{NMR (CDCl 3): 0.679 (} C 18 H 3), 1.343 (C 19 H 3), 3.0
0 (17-OH), 3.78 (COOCH 3), 5.55 (C 11 H), 5.74 (C
⁴ H).

 ──────────────────────────────────────────────────続 き Continued on front page (72) Inventor Arthur Friedrich Marx The Netherlands 2614 Heem Delft Florence Nightingalelan 12

Claims (4)

(57) [Claims] 1. An androstan or pregnane 9
(11) A method for producing a dehydrosteroid by dehydration of a corresponding 9-α-hydroxysteroid,
A method comprising performing the dehydration reaction in the presence of a Lewis acid. 2. The method according to claim 1, wherein the Lewis acid is selected from the group consisting of ferric chloride, boron trifluoride or complexes thereof, antimony pentachloride, titanium tetrachloride and mixtures of silicon dioxide and their compounds. the method of. 3. The method according to claim 1, wherein the Lewis acid is a boron trifluoride complex. 4. The method according to claim 1, wherein the reaction is carried out in an inert organic solvent at room temperature to reflux temperature.